Methods for Alleviating Statin Myopathy

ABSTRACT

Disclosed herein are methods and compositions for alleviating side effects of statin administration, such as myopathic or myalgic side effects, short-term memory loss, abnormal liver function, glucose intolerance, hyperglycemia, increased risk for diabetes, or cumulative trauma disorder, comprising administration of β-hydroxy β-methylbutyrate (HMB) to an individual taking a statin. Also disclosed are methods and compositions for alleviating acute rhabdomyolysis comprising administration of HMB. The disclosure further provides uses of HMB in combination with a statin to alleviate side effects of statin administration.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/971,072, filed Mar. 27, 2014, the disclosure of which is incorporatedby reference herein in its entirety.

BACKGROUND OF THE INVENTION

HMG-CoA reductase inhibitors, commonly known as statins, are a class ofdrugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoAreductase, which catalyzes the rate-limiting conversion of HMG-CoA intomevalonate by HMG-CoA reductase during de novo cholesterol biosynthesis.Statins are used primarily to treat hyperlipidemias and are the mosteffective lipid-lowering drugs currently available. They have also beenshown to exhibit pleiotropic effects and may have potential uses in thetreatment of other conditions, such as diabetes, depression, cancer,osteoporosis, ventricular arrhythmias, peripheral arterial disease, andidiopathic dilated cardiomyopathy.

Side effects of statins include myopathy (including myalgia), increasedrisk of diabetes, short-term memory loss, cumulative trauma disorder,and abnormalities in liver enzyme tests. Myopathy is the most commonside effect, with symptoms that can include muscle fatigue, weakness,pain, and rhabdomyolysis (i.e., the breakdown of muscle fibers thatleads to the release of muscle fiber contents (inter alia, myoglobin)into the bloodstream). Rhabdomyolysis is rare, occurring in ˜0.1% ofpatients; the occurrence of other myopathic symptoms has been estimatedat 1-5% of patients in controlled studies using selected patients with35% of eligible patients excluded (LaRosa et al., New England Journal ofMedicine 2005, 352: 1425-35). An observational study (PRIMO) involving7924 French unselected outpatients on statin therapy, reported 10.5% ofstatin users experienced statin-related myalgia/myopathy (Bruckert etal., Cardiovascular Drugs and Therapy 2005, 19: 403-14). Otherobservational studies have estimated that 9-20% of statin usersexperience statin-related muscle symptoms. Physical exercise appears toexacerbate the incidence of myalgia, with as many as 25% of statin userswho exercise experiencing muscle fatigue, weakness, aches, and cramping.

Thus, there is a need in the art to improve treatment of statin-relateddiseases and disorders by alleviating said deleterious side effects.

SUMMARY OF THE INVENTION

This disclosure provides certain advantages and advancements over theprior art, in particular, methods for alleviating statin-inducedmyopathy and/or myalgia (SIM) comprising administering β-hydroxyβ-methylbutyrate (HMB) to an individual taking a statin. In alternativeembodiments, the disclosure provides methods for alleviating myopathyand/or myalgia, such as acute rhabdomyolysis, in individuals not takinga statin comprising administering HMB.

In one aspect, the disclosure provides methods for alleviating one ormore side effects of statin administration, comprising supplementingstatin administration with administration of a therapeutically effectiveamount of β-hydroxy β-methylbutyrate (HMB). In some embodiments, the oneor more side effects of statin administration are any one or a pluralityof myopathic or myalgic side effects, short-term memory loss, abnormalliver function, glucose intolerance, hyperglycemia, increased risk fordiabetes, or cumulative trauma disorder. In some embodiments, HMB isadministered at a dosage of approximately 1 to 6 grams/day, or otherwiseat a dosage of approximately 2 to 4 grams/day. In some embodiments, HMBis administered at a dosage of approximately 3.0 grams/day. In someembodiments, HMB is administered at a dosage of approximately 2 gramstaken twice a day. In particular embodiments, the invention providespharmaceutical formulations of HMB comprising a therapeuticallyeffective amount thereof and pharmaceutically acceptable excipients,diluents, or other formulating agents. In some embodiments, the statinis atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin, or simvastatin. In someembodiments, the statin is rosuvastatin.

In another aspect, the disclosure provides methods for alleviating acuterhabdomyolysis, comprising administering a therapeutically effectiveamount of β-hydroxy β-methylbutyrate (HMB).

In another aspect, the disclosure provides pharmaceutical formulationscomprising a statin and a myopathic or myalgic statin sideeffect-alleviating amount of β-hydroxy β-methylbutyrate (HMB). In someembodiments, the statin is atorvastatin, cerivastatin, fluvastatin,lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, orsimvastatin. In some embodiments, the statin is rosuvastatin.

In another aspect, the disclosure provides uses of HMB in combinationwith a statin to alleviate one or more side effects of statinadministration. In some embodiments, the one or more side effects ofstatin administration are myopathic or myalgic side effects, short-termmemory loss, elevated alanine transaminase (ALT) or aspartatetransaminase (AST) levels, glucose intolerance, hyperglycemia, increasedrisk for diabetes, or cumulative trauma disorder. In some embodiments,the statin is atorvastatin, cerivastatin, fluvastatin, lovastatin,mevastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin.

These and other features and advantages of the present invention will bemore fully understood from the following detailed description of theinvention taken together with the accompanying claims. It is noted thatthe scope of the claims is defined by the recitations therein and not bythe specific discussion of features and advantages set forth in thepresent description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of the embodiments of the presentinvention can be best understood when read in conjunction with thefollowing drawings, in which:

FIG. 1 is a schematic of the human cholesterol biosynthesis pathway.Statins inhibit the initial step (conversion of HMG-CoA to mevalonicacid by HMG-CoA reductase), thereby preventing the downstream metaboliccascade. HMB reverses this inhibition, allowing isoprenoid production,the ubiquinone pathway and on-site myocyte cholesterol synthesis toproceed.

FIG. 2 shows the structure of a mammalian cell membrane. Cholesterol isan integral cell membrane component and is synthesized in situ tomaintain cellular structural integrity, particularly in myocytes. Insitu cholesterol biosynthesis is a process inhibited by statins butpromoted by HMB.

FIG. 3A shows the chemical structure of cholesterol. FIG. 3B shows amolecular stick model of cholesterol.

FIG. 4 depicts a molecule of cholesterol between two phospholipidmolecules within a lipid bilayer.

FIG. 5 is a schematic of some elements of leucine, α-ketoisocaproate(KIC), and HMB metabolism in mammals, which comprises an alternativepathway in the myocyte for production of HMG CoA. HMB is converted toHMB-CoA, then to β-hydroxy-β-methylglutaryl-CoA (HMG-CoA), theconversion of which into mevalonate is catalyzed by HMG-CoA reductase.Mevalonate is eventually converted into cholesterol, as shown in FIG. 1.MC-CoA refers to β-methyl-crotonyl-CoA; MG-CoA refers toβ-methyl-gluconyl-CoA.

Skilled artisans will appreciate that elements in the Figures areillustrated for simplicity and clarity and have not necessarily beendrawn to scale. For example, the dimensions of some of the elements inthe Figures can be exaggerated relative to other elements to helpimprove understanding of the embodiment(s) of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

All publications, patents and patent applications cited herein arehereby expressly incorporated by reference for all purposes.

Before describing the present invention in detail, a number of termswill be defined. As used herein, the singular forms “a”, “an”, and “the”include plural referents unless the context clearly dictates otherwise.For example, reference to a “protein” means one or more proteins.

It is noted that terms like “preferably”, “commonly”, and “typically”are not utilized herein to limit the scope of the claimed invention orto imply that certain features are critical, essential, or evenimportant to the structure or function of the claimed invention. Rather,these terms are merely intended to highlight alternative or additionalfeatures that can or cannot be utilized in a particular embodiment ofthe present invention.

For the purposes of describing and defining the present invention it isnoted that the term “substantially” is utilized herein to represent theinherent degree of uncertainty that can be attributed to anyquantitative comparison, value, measurement, or other representation.The term “substantially” is also utilized herein to represent the degreeby which a quantitative representation can vary from a stated referencewithout resulting in a change in the basic function of the subjectmatter at issue.

As used herein, the term “statin” refers to a 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitor. Statins block therate-limiting step in de novo cholesterol biosynthesis, namely, theconversion of HMG-CoA into mevalonate by HMG-CoA reductase. Statins areused primarily as cholesterol-lowering (specifically, low-densitylipoprotein (LDL)-lowering) medications to treat hyperlipidemias, suchas hypercholesterolemia. Examples of statins with brand names andtypical daily adult dose ranges provided in parentheses include:atorvastatin (LIPITOR®) (10-80 mg), fluvastatin (LESCOL®) (20-80 mg),lovastatin (MEVACOR®) (10-80 mg), pitavastatin (LIVALO®) (1-4 mg),pravastatin (PRAVACHOL®) (10-80 mg), rosuvastatin (CRESTOR®) (5-20 mg),and simvastatin (ZOCOR®) (5-80 mg).

The following disclosure is provided without being limited to anymechanism and solely to explicate what is understood in the artregarding statin-mediated decrease in circulating LDL. LDL-B(apo-lipoprotein B) is a lipid carrier molecule, manufactured in theliver, that is highly atherogenic. LDL-B levels are regulated by liverLDL receptors that bind to circulating LDL particles, resulting in theirabsorption and ultimate destruction in liver. The greater the density ofLDL receptor sites on liver cell (hepatocyte) surfaces, the lower thelevel of LDL-B cholesterol in circulation. PCSK9 (proprotein convertasesubtilisin/kexin type 9) is a glycoprotein expressed by the liver thatdegrades LDL receptors. When this occurs, LDL-B levels rise incirculation. Statins, by inhibiting HMG CoA reductase, reduceintra-cellular cholesterol production in the hepatocyte, in turnactivating SREBP-2 (sterol regulatory element binding protein-2). Thispathway then upregulates hepatic LDL receptor sites, increasing liverclearance of circulatory LDL-B. Although statins also upregulate PCSK9levels by 7%, this increase is more than offset by the upregulation ofSREBP-2, resulting in a net decrease in LDL B particles in solution.

Statins also exert an effect on myocytes (skeletal muscle cells) byinterfering with intra-cellular cholesterol synthesis, an activity thathas no relationship to circulating LDL-B levels. HMB is a metabolite ofan essential amino acid (branch chain amino acid leucine), and while itis taken up by myocytes it is not stored in hepatocytes. For thisreason, HMB can unexpectedly be used concurrently with statin agentswithout subverting the hepatic effect of statins in lowering LDL-Bcholesterol.

As used herein, the terms “side effect,” “peripheral effect,” and“secondary effect” are interchangeable and refer to effects or symptomscaused by a drug, medication, or pharmaceutical other than its primary,intended effect or indication.

As used herein, the terms “myopathy” and “myopathic” refer to muscledamage, dysfunction, or disease wherein muscle fibers do not functionproperly for any one of many reasons, resulting in, for example, muscleweakness, muscle cramps, muscle spasms, muscle stiffness, or elevationof creatine kinase (CK or CPK) levels in blood. For example, myositismay be assessed when CK levels rise above a certain amount, such asabove a 1 to 10-fold “upper limit of normal” (ULN). In some cases,muscle symptoms might be observed without a concomitant elevation in CKlevels. In other cases, CK levels might be elevated without musclesymptoms.

As used herein, the term “rhabdomyolysis” refers to a type of myopathyinvolving the release of muscle cell products into the bloodstreamfollowing muscle cell damage. Some of these muscle cell products, suchas myoglobin, are harmful to the kidneys and may lead to kidney damageor kidney failure. Rhabdomyolysis can also result in disseminatedintravascular coagulation and/or death. Rhabdomyolysis might be defined,for example, by CK levels above 10,000 IU/liter or above a 10-fold ULNwith an elevation in serum creatinine or a need for hydration therapy.Rhabdomyolysis may be statin-induced or non-statin-induced. For example,in some cases rhabdomyolysis is induced by intense exercise. In someembodiments of the methods disclosed herein, HMB administration is usedto treat rhabdomyolysis induced by statin administration. In someembodiments, HMB administration is used to treat non-statin-inducedrhabdomyolysis.

As used herein, the terms “myalgia” and “myalgic” refer to muscle pain,which may be a symptom of many diseases and disorders, includingmyopathy.

Myopathy and/or myalgia are the most common side effects associated withthe use of statins. Symptoms of statin-induced myopathy include anycombination of muscle pain, muscle weakness, or muscle tenderness, suchas an aching or cramping sensation in muscles. Tendon pain and nocturnalleg cramping are other possible symptoms. Statin-induced myopathies aretypically exacerbated by exercise; thus, athletes are frequentlyparticularly intolerant to statin therapy. The incidence ofstatin-induced myopathy or myotoxicity is estimated as about 1.5-5% inrandomized-control clinical trials.

The pathology of statin-induced myopathy is not fully understood,particularly because multiple pathophysiological mechanisms maycontribute to statin myotoxicity. Without being limited to these or anyother explanations of how the invention may work or the biochemical orphysiological mechanisms or explanations thereof, these mechanismsinclude statin-induced alterations in muscular membrane composition,isoprenoid and ubiquinone synthesis, mitochondrial function, calciumhomeostasis, rate of apoptosis, and atrogin-1 induction.

The lipid bilayer of many cell membranes consists not only ofphospholipids, but also cholesterol and glycolipids. Eukaryotic plasmamembranes contain especially large amounts of cholesterol—up to onecholesterol molecule for every phospholipid molecule. Cholesterol isthus an integral cell membrane component. Cholesterol molecules enhancethe permeability-barrier properties of the lipid bilayer and modulatethe fluidity of cell membranes, including the membranes of muscle cells.Membrane-bound cholesterol molecules orient themselves in the bilayerwith their hydroxyl groups (FIGS. 3A and 3B) toward the polar headgroups of the phospholipid molecules (FIG. 4). In this position,cholesterol's rigid, plate-like steroid rings interact with—and partlyimmobilize—those regions of the phospholipid hydrocarbon chains closestto the polar head groups. By decreasing the mobility of the first fewCH₂ groups of the phospholipid hydrocarbon chains, cholesterol makes thelipid bilayer less deformable in this region and thereby decreases thepermeability of the bilayer to small water-soluble molecules. Althoughcholesterol tends to make lipid bilayers less fluid at the highconcentrations found in most eukaryotic plasma membranes, it alsoprevents component hydrocarbon chains from coming together andcrystallizing. In this way, it inhibits possible phase transitions.Because statins interfere with cholesterol biosynthesis, they alsoaffect myocyte membrane fluidity. Alterations in membrane fluidity inturn can affect membrane ion channel function, which plays an integralrole in membrane excitability. For example, chloride channels inskeletal muscle membranes control resting membrane potential andmembrane repolarization. Thus, statin-induced depletion of cholesterollikely disturbs muscle cell function.

According to the isoprenoid synthesis mechanism, statins may causemyopathy by inhibiting synthesis of isoprenoids, for which mevalonate isa precursor. Statin-induced depletion of isoprenoids may in turn disturbcellular respiration, causing myopathy. Under the calcium homeostatistheory of statin-induced myopathy, statin-mediated depletion ofisoprenoids leads to decreased inhibition of calcium ion (Ca²⁺) channelsin muscle cells, which results in impaired calcium ion homeostasis andimpaired myocyte function. Other possible mechanisms of statin-inducedmyopathy are related to statins' “pleiotropic effects,” which arecholesterol-independent effects of statins. These pleiotropic effectsinclude statin-mediated improvement in endothelial function,stabilization of atherosclerotic plaques, decreases in oxidative stressand inflammation, and inhibition of thrombogenic responses. However,statins can also trigger skeletal muscle apoptosis (i.e. programmed celldeath) and, thus, myopathy. Statin-induced myopathy may also be causedthrough induction, by any statin, of atrogin-1, a human gene thatinduces muscle pathology directly and is activated by inhibition of thegeranasylgeranasyl isoprenoid pathway, part of the cholesterol synthesiscascade obstructed by statins. (See Cao et al., 2009, FASEB J.23(9):2844-54.)

Statin myopathy appears only in a subset of muscle fibers. In general,the human body consists of a 1:1 ratio of Type 1 (aerobic, slow-twitch)muscle fibers and Type 2 (anaerobic, fast-twitch) muscle fibers. Allmuscle fibers require cholesterol for cellular repair. Type 2 fibersexpress LDL receptors, which enable absorption of circulatingcholesterol (see Takeda et al., Pathobiology, 2014, 81:94-99). Type 1fibers, which are used in ordinary activities such as standing andwalking, lack LDL receptors and are thus dependent on intracellularcholesterol synthesis, a process inhibited by statin agents. Theresulting deficit in cellular cholesterol in Type 1 fibers can lead tostatin myopathy.

As used herein, the terms “HMB,” “β-hydroxy β-methylbutyric acid,”“β-hydroxy β-methylbutyrate,” “3-hydroxy-3-methylbutanoic acid,”“3-hydroxy 3-methyl butyrate,” “β-hydroxyisovaleric acid,” and“3-hydroxyisovaleric acid” are interchangeable and refer to the compoundof formula (I):

HMB is a metabolite of the amino acid leucine and is synthesized in thehuman body, where it is converted into the cholesterol precursorHMG-CoA. HMB is used as a dietary supplement by athletes andbodybuilders to enhance performance and training. Daily doses of HMB asa dietary supplement range from about 2 to 5 grams per day, morecommonly about 3 grams per day. In terms of dose per body mass, dailydoses of HMB as a dietary supplement range from about 17 mg/kg bodyweight to about 38 mg/kg body weight. Daily HMB dietary supplementdosages can be divided up into, for example, one to four administrationsper day.

The role of HMB in metabolism of leucine into cholesterol is shown inFIG. 5. It takes about 60 grams of leucine to produce 1 gram of HMB;therefore, leucine supplements are ineffective as a source of HMB.

Toxicologically, the “No Observed Adverse Effect Level” (NOAEL; thehighest dose not associated with any toxic signs) for HMB oral ingestionin rats is 3490 mg/kg for male rats and 4160 mg/kg for female rats (seeBaxter et al., Chem Toxicol., 2005, 43(12):1731-41). This is anestimated human equivalent of 558 mg/kg and 665 mg/kg for men and women,respectively; assuming a body weight of 150 lbs equates to 38 g (males)and 45 g (females). Human toxicological studies have shown thatapproximately 6 g HMB daily (78 mg/kg) for one month in untrained youngmales subject to exercise did not show any toxic effects on serumparameters (half the dose had a spontaneous increase in basophils,considered to be insignificant) and 3 g of HMB daily for up to 8 weeksin both youth and older persons has similarly failed to altertoxicological parameters in serum. This dose has been shown to be safefor one year of administration (see Gallagher et al., Med Sci SportsExerc., 2000 December; 32(12):2116-19; Nissen et al., J Nutr., 2000August;130(8):1937-45). Overall, standard doses of HMB appear to bewell-tolerated over long periods of time.

As the person of ordinary skill in the art will appreciate, HMB can beprovided as an HMB derivative or prodrug, depending, e.g., on thedesired end properties of the compositions and methods. For example, HMBmay be modified with a suitable prodrug group that metabolizes orotherwise transforms under conditions of use to yield HMB. In oneembodiment, HMB may be modified at the carboxylic acid moiety with asuitable group that can be hydrolyzed. In these embodiments, HMB isprovided for example as an ester or a lactone. Suitable HMB estersinclude, but are not limited to, methyl ester, ethyl ester, andisopropyl ester. Exemplary, non-limiting HMB lactone includes isovalaryllactone. HMB may also be modified at the hydroxy moiety, for example,with an acetate group. HMB derivatives to be used for the compositionsand methods of the present disclosure are within the skill of the personskilled in the art using routine trial and experimentation. In someembodiments, HMB derivatives or prodrugs are used in the compositionsand methods disclosed herein in order to provide delayed or sustainedrelease of HMB.

As used herein, the term “hydrate” refers to a compound that iscomplexed with at least one water molecule. For example, HMB monohydraterefers to a molecule of HMB complexed with one water molecule.

As used herein, the term “alleviate” refers to the amelioration orlessening of the severity of a side effect or symptom or substantiallyeliminating said side effect or symptom.

As used herein, the term “administer” or “administration” refers to oral(“po”) administration, administration as a suppository, topical contact,intravenous (“iv”), intraperitoneal (“ip”), intramuscular (“im”),intralesional, intranasal or subcutaneous (“sc”) administration, or theimplantation of a slow-release device e.g., a mini-osmotic pump, to anindividual. Administration can be by any route including parenteral andtransmucosal (e.g., oral, nasal, vaginal, rectal, or transdermal).Parenteral administration includes, e.g., intravenous, intramuscular,intra-arteriole, intradermal, subcutaneous, intraperitoneal,intraventricular, and intracranial. Other modes of delivery include, butare not limited to, the use of liposomal formulations, intravenousinfusion, transdermal patches, and equivalent methods and modalitiesknow to those of skill in the art.

As used herein, the term “co-administer” refers to administering morethan one pharmaceutical agent to a patient. In some embodiments,co-administered pharmaceutical agents are administered together in asingle dosage unit. In some embodiments, co-administered pharmaceuticalagents are administered separately. In some embodiments, co-administeredpharmaceutical agents are administered at the same time. In someembodiments, co-administered pharmaceutical agents are administered atdifferent times.

The term “pharmaceutical formulation” refers to a preparation which isin such form as to permit a biological activity of an active ingredientto be effective, and which contains no additional components which areunacceptably toxic to a subject to which the formulation would beadministered.

As used herein, the terms “extended release,” “sustained release,” or“controlled release” refer to compositions that are characterized byhaving at least one active component having a release profile over anextended period of time, in contrast to “immediate release”pharmaceutical formulations. In some embodiments, the compositionsdisclosed herein release their active components over a period of about6 hours to about 72 hours, or about 12 hours to about 48 hours, or about12 hours to about 36 hours, or about 18 hours to about 30 hours, orabout 24 hours. In some embodiments, the active component is releasedover a time period such that the composition can be administered to asubject once a day, for example, over 24 hours.

In some embodiments, the active ingredients of the compositions andmethods disclosed herein are formulated in free acid or free base form.For example, in some embodiments, HMB is formulated as HMB free acid. Insome embodiments, HMB free acid is administered orally or sublinguallyas a gel.

In some embodiments, the active ingredients of the compositions andmethods disclosed herein are formulated as a pharmaceutically acceptablesalt. As used herein, the term “pharmaceutically acceptable salt” refersto salts of the compounds of the present invention derived from thecombination of such compounds and a pharmaceutically acceptable organicor inorganic acid (acid addition salts) or a pharmaceutically acceptableorganic or inorganic base (base addition salts) which retain thebiological effectiveness and properties of the compounds of the presentinvention and which are not biologically or otherwise undesirable.Examples of pharmaceutically acceptable salts include but not limited tothose described in for example: “Handbook of Pharmaceutical Salts,Properties, Selection, and Use”, P. Heinrich Stahl and Camille G.Wermuth (Eds.), Published by VHCA (Switzerland) and Wiley-VCH (FRG),2002. The compounds of the present invention may be used in either thefree base or salt forms, with both forms being considered as beingwithin the scope of the present invention. For example, HMB may beadministered as a salt selected from the group consisting of a sodiumsalt, a potassium salt, a magnesium salt, a chromium salt, and a calciumsalt. Other non-toxic salts, such as other alkali metal or alkalineearth metal salts can be used. In some embodiments, HMB may beadministered as calcium HMB monohydrate. Other salts which may act ascarriers include succinate, fumarate and medoximil.

Extended release salts such as succinate may be bound to HMB such thatthe HMB is released at a controlled rate. In some embodiments, HMB isreleased at a rate such that the HMB can be administered once a day. HMBhas a relatively short half-life and reaches peak levels quickly.Therefore, binding HMB to a slow release carrier may have some utilityin terms of compliance and efficacy.

HMB may be combined with any of the above-mentioned statins to providecombination lipid lowering therapy in patients who are otherwise statinintolerant. Examples would include HMB/atorvastatin, HMB/rosuvastatin,HMB/pravastatin, HMB/simvastatin and HMB/lovastatin.

In one aspect, the disclosure provides methods for alleviating one ormore side effects of statin administration, the method comprisingsupplementing statin administration with administration of atherapeutically effective amount of β-hydroxy β-methylbutyrate (HMB),wherein one or more side effects of statin administration arealleviated. In some embodiments, the one or more side effects of statinadministration are one or a plurality of myopathic or myalgic sideeffects, short-term memory loss, abnormal liver function, glucoseintolerance, hyperglycemia, increased risk for diabetes, or cumulativetrauma disorder. In some embodiments, the myopathic or myalgic sideeffects include muscle fatigue, muscle weakness, muscle pain, and/orrhabdomyolysis. In some embodiments, the rhabdomyolysis is acuterhabdomyolysis.

As used herein, the phrase “abnormal liver function” refers to liverfunction characterized by elevated liver functions tests (LFTs), and inparticular, elevations in levels of alanine transaminase (ALT, alsoknown as SGPT) and/or aspartate transaminase (AST, also known as SGOT)enzymes. Elevated ALT and AST levels are indicators of liver damage.Other terms for this condition include transaminasemia andtransaminitis. LFTs are “elevated” when above the normal ranges, whichare about 8-40 U/L for ALT and AST.

As used herein, the phrase “glucose intolerance” refers to a metaboliccondition resulting in higher-than-normal levels of blood glucose.Glucose intolerance can include type 1, type 1.5, and type 2 diabetes.Measurement of glycated hemoglobin levels (hemoglobin A1c or HbA1c) in apatient is one way to assess glucose intolerance and/or diabetes. Forpeople without diabetes, the normal range for the hemoglobin A1c test isbetween 4% and 5.6%. Hemoglobin A1c levels between 5.7% and 6.4%indicate increased risk of diabetes, and levels of 6.5% or higherindicate diabetes. Thus, in some embodiments of the methods disclosedherein, glucose intolerance is characterized by hemoglobin A1c levels ator exceeding about 5.6%, or about 5.7%, or about 6.4%, or about 6.5%.

In some embodiments of the methods disclosed herein, the HMB isadministered at a dosage of about 0.5 to about 10 grams/day, or of about1.0 to about 6.0 grams/day, or of about 2.0 to 4.0 grams/day. In someembodiments, the HMB is administered at a dosage of approximately 4grams/day. In some embodiments, the HMB is administered at a dosage ofapproximately 3 grams/day. In some embodiments, the HMB is administered1 to 5 times per day. In some embodiments, the HMB is administered 3times per day. In some embodiments, the HMB is administered 2 times perday. In some embodiments, the HMB is administered 1 time per day.

In some embodiments, HMB is administered as a calcium salt, such ascalcium HMB monohydrate. In some embodiments, HMB is administered as HMBfree acid.

In some embodiments of the methods disclosed herein, HMB is administeredin an extended-release form. In some embodiments, the extended-releaseform of HMB comprises succinate in order to extend release time in thegastrointestinal tract. In some embodiments, extended-release forms ofHMB are designed or formulated to be administered one to three times perday. In some embodiments, extended-release forms of HMB are formulatedto be administered once per day.

In some embodiments of the methods disclosed herein, the statin isatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin, or simvastatin. In someembodiments, the statin is rosuvastatin.

In another aspect, the disclosure provides methods for treating acuterhabdomyolysis comprising administering a therapeutically effectiveamount of HMB. In some embodiments, the acute rhabdomyolysis is notstatin-induced. For example, acute rhabdomyolysis is caused bydehydration, trauma, and/or intense exercise. In some embodiments, HMBis administered at a dosage of from about 3 grams/day to about 15grams/day. In some embodiments, HMB is administered at a dosage of about12 grams/day. In some embodiments, HMB is administered at a dosage of 6grams twice a day. In some embodiments, HMB is HMB free acid. In someembodiments, HMB is administered for at least three days.

In another aspect, the disclosure provides pharmaceutical formulationscomprising a statin and a myopathic or myalgic statin sideeffect-alleviating amount of β-hydroxy β-methylbutyrate (HMB). In someembodiments of the pharmaceutical formulations disclosed herein, themyopathic or myalgic statin side effect-alleviating amount of HMBcomprises a dosage of HMB of about 0.5 to about 10 grams/day, or ofabout 1.0 to about 6.0 grams/day, or of about 2.0 to 4.0 grams/day. Insome embodiments, myopathic or myalgic statin side effect-alleviatingamount of HMB comprises a dosage of approximately 3.0 grams/day. In someembodiments, the HMB is HMB monohydrate. In some embodiments, the HMB isHMB calcium salt.

In some embodiments of the pharmaceutical formulations disclosed herein,the statin is atorvastatin, cerivastatin, fluvastatin, lovastatin,mevastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin. Insome embodiments, the statin is rosuvastatin. In some embodiments, theratio of statin to HMB is approximately 0.001 to 0.1 by weight. In someembodiments, the ratio of statin to HMB is about 0.008, or about 0.01,or about 0.02, or about 0.03, or about 0.04, or about 0.05, or about0.06, or about 0.07, or about 0.08, or about 0.09 by weight. In someembodiments, the ratio of statin to HMB is approximately 0.01 by weight.In some embodiments, the amount of HMB is from about 1.0 gram to about4.0 grams.

In some embodiments of the pharmaceutical formulations disclosed herein,HMB is formulated for extended release. In some embodiments,extended-release forms of HMB comprise succinate in order to extendrelease time in the gastrointestinal tract. In some embodiments,extended-release forms of HMB are designed or formulated to beadministered one to three times per day. In some embodiments,extended-release forms of HMB are formulated to be administered once perday.

In another aspect, the disclosure provides uses of HMB in combinationwith a statin to alleviate one or more side effects of statinadministration. In some embodiments, the one or more side effects ofstatin administration are one or a plurality of myopathic or myalgicside effects, short-term memory loss, abnormal liver function, glucoseintolerance, hyperglycemia, increased risk for diabetes, or cumulativetrauma disorder. In some embodiments, the myopathic or myalgic sideeffects include muscle fatigue, muscle weakness, muscle pain, and/orrhabdomyolysis. In some embodiments, the rhabdomyolysis is acuterhabdomyolysis.

In some embodiments of the uses disclosed herein, the HMB isadministered at a dosage of about 0.5 to about 15 grams/day, or of about1.0 to about 6.0 grams/day, or of about 2.0 to 4.0 grams/day. In someembodiments, the HMB is administered at a dosage of approximately 4grams/day. In some embodiments, the HMB is administered at a dosage ofapproximately 3 grams/day. In other embodiments, the HMB is administeredat a dosage of about 3.0 to about 15.0 grams/day. In some embodiments,the HMB is administered at a dosage of about 12.0 grams/day. In someembodiments, the HMB is administered 1 to 5 times per day. In someembodiments, the HMB is administered 3 times per day. In someembodiments, the HMB is administered 2 times per day. In someembodiments, the HMB is administered 1 time per day. In someembodiments, HMB is administered as a calcium salt, such as calcium HMBmonohydrate. In some embodiments, HMB is administered as HMB free acid.

In some embodiments of the uses disclosed herein, HMB is administered inan extended-release form. In some embodiments, the extended-release formof HMB comprises succinate in order to extend release time in thegastrointestinal tract. In some embodiments, extended-release forms ofHMB are designed or formulated to be administered one to three times perday. In some embodiments, extended-release forms of HMB are formulatedto be administered once per day.

In some embodiments of the uses disclosed herein, the statin isatorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,pitavastatin, pravastatin, rosuvastatin, or simvastatin. In someembodiments, the statin is rosuvastatin.

EXAMPLES

The Examples that follow are illustrative of specific embodiments of theinvention, and various uses thereof. They are set forth for explanatorypurposes only, and are not to be taken as limiting the invention.

Example 1 Initial Assessment of HMB Reversal of Statin Myalgia

A healthy, fully informed and consenting adult volunteer with severerosuvastatin-induced myalgia and myopathy and pre-statin LDL of 260 wasadministered 1 gram HMB three times a day (3 grams/day total) whilerosuvastatin therapy was continued. Within 72 hours of the initial HMBadministration, statin myalgia/myopathy fully subsided. During briefintervals where HMB treatment was discontinued (i.e., unintentionallyskipped doses), the subject reported a return of myalgia, which againsubsided upon reinstatement of HMB treatment. An increase in HMB dosageto 6 grams/day provided no additional benefit.

Example 2 Clinical Study Evaluating the Effects of HMB Therapy onPatients with Statin-Induced Myopathy

A clinical study was conducted to evaluate the effects of HMB onpatients with statin-induced myopathy (SIM). A total of eighteenpatients were evaluated for the study with informed written consentobtained. Of the eighteen patients, fourteen (14) ultimately qualifiedas having true statin myalgia and were enrolled in the study. Allpatients enrolled were under the care of a board certified cardiologist.

A summary of the enrolled patients and their outcomes is as follows:

-   -   1. All 14 had type 2a or mixed hyperlipidemia.    -   2. All 14 had been treated with multiple statin agents, in each        case withdrawing from the statin agent due to myalgia/myopathy.    -   3. Of the 14 patients enrolled, 4 had elevated CPKs (creatine        phosphokinase, a biomarker for myositis/rhabdomyolysis)        secondary to SIM.    -   4. Five of the 14 patients had undergone prior percutaneous        coronary intervention with stents.    -   5. One of the 14 patients had undergone prior coronary bypass        surgery.    -   6. Four of the 14 patients had angiographically documented        moderate coronary artery disease not requiring percutaneous        coronary intervention (PCI)/coronary bypass.    -   7. Four of the 18 patients were disqualified due to the        following:        -   Patient's leg myalgia was secondary to angiographically            proven peripheral vascular disease, not SIM and symptoms            were consistent with this diagnosis.        -   Patient's unilateral leg pain was secondary to neuropathy,            not SIM.        -   Patient complained of GI upset on combined statin+3-hydroxy            3-methybutyrate and medication was discontinued. Of note,            the patient's SIM-related myalgia resolved completely after            HMB treatment.        -   Patient presentation and clinical course were ultimately            incompatible with statin myopathy.    -   8. All 14 qualified patients remained on combination statin (in        some cases with

Zetia to achieve target) plus HMB therapy after the initial duration ofthe study. As noted, of those who had previously discontinued statintherapy, all had been tried on multiple statin agents without success.

-   -   9. Follow up was conducted with all patients including        out-patient visits and phone conversation.    -   10. All 14 qualifying patients responded to therapy with        complete resolution of SIM symptoms.

Two available forms of HMB were utilized in this study: calciummonohydate form as a powder and free acid (which is more bioavailable)form as a gel cap. The free acid form was used in one patient whoexperienced major CPK elevations (900-1000 IU/L range) and disablingmyalgia on statins. The free acid form resulted in a significantdecrease in CPK and resolution in symptoms with an improvement over thecalcium monohydrate form (see summary for Patient D-4, below).

For this study, patients were evaluated using multiple laboratories withvariable lab normal ranges, which are included. In the patientpopulation as a whole, the full spectrum of SIM is presented, includingstatin myalgia without CPK elevation (myositis or rhabdomyolysisdepending on severity), elevation of CPK without myalgia, post-statinelevation of CPK with and without pain, post-statin myalgia without CPKelevation, and, finally, statin-induced muscle weakness without myalgia.Also represented were other statin-induced side effects such asshort-term memory loss and glucose intolerance.

Clinical summaries for patients enrolled in the study are providedbelow.

Patient A-1

53 year old female, diagnosed three years prior by her primary physicianwith severe hyperlipidemia, apparently mixed-type. She was otherwise ingood health. Simvastatin was prescribed with resultant severe bilateralleg myopathy/myalgia. The patient's internist substituted Crestor®(rosuvastatin) for simvastatin with the hope of alleviating thepatient's leg pain. The pain intensified and persisted, involving thequadriceps, gluteals, and pyriformis muscles bilaterally. She stoppedCrestor® on her own accord but the pain abated only minimally and shewas having difficulty walking. Six weeks after stopping Crestor®, stillin pain, her CPK was elevated (242 IU/L, lab normal range 26-192)consistent with a persistent post-statin myositis. At that time, she wasnot physically active. She was placed on calcium HMB monohydrate, 2 gBID (twice daily) prior to re-introducing statin therapy. All paincompletely resolved in 3 days. A repeat CPK was drawn 9 days later andwas in normal range (87 IU/L, range 26-192). Subsequently, Crestor® at adose of 10 mg daily was prescribed. The patient remained completely painfree after 3 months on statin therapy despite regularly exercising atthe gym with a weights/cardio regimen. Subsequent lab results confirmedmixed rather than a pure type 2a hyperlipidemia, with triglycerides >400mg %. Vascepa was added to her statin regimen along with acarbohydrate-restricted diet and regular exercise. Patient re-evaluation3 months after beginning treatment with HMB: asymptomatic, no recurrenceof leg, hip myalgia or biomarker (+) myositis on Crestor®, 10 mgdaily+calcium HMB monohydrate 2 g BID. LDL=72 mg/dl. CPK=110 IU/L.

Patient B-2

60 year old male, with coronary heart disease, having undergonepercutaneous coronary intervention with stent 10 years prior. PatientB-2 was statin intolerant and previous attempts on statin therapy hadfailed due to intractable leg myalgia. An alternative regimen ofWelchol®, 6 tablets daily and Zetia®, 10 mg daily was prescribed withrelief of myalgia. Prior to beginning HMB therapy, B-2 had elevated LDL=168 mg % on this combination non-statin therapy. Welchol® wasdiscontinued and he was placed on Vytorin®, 10/40+calcium HMBmonohydrate, 2 g BID. Repeat lab 50 days later demonstrated a drop inLDL to 110 mg % with a normal CPK (173 IU/L, lab normal range 44-196).Six months later, the patient remained compliant with his medication andremained completely asymptomatic on Vytorin®.

Patient C-3

Male, age 52, with medical problems that included type 2ahyperlipidemia, type 2 diabetes, hypertension and a benign mitral valvedisorder. Multiple attempts at statin therapy on a variety of statinsmet with almost immediate failure due to statin intolerance in the formof myalgia, relieved only by discontinuing the statin. Zetia® asmonotherapy was prescribed with modest success but he was unable toachieve clinical goals (<100 mg % LDL) for a diabetic patient. Thepatient was placed on Crestor®, 10 mg daily +calcium HMB monohydrate, 2g BID. Three months later, he remained completely symptom free on statintherapy.

Patient D-4

Female, age 61, diagnosed with severe hyperlipidemia, small vesselcoronary artery disease by cardiac catheterization, type 2 diabetes,hypertension and hypothyroidism, all of which were under medicalmanagement, including injectable Victoza® and Lantus® insulin fordiabetes. Patient historically was statin intolerant with statin myalgiabut multiple coronary risk factors and known coronary disease mandatedLDL control. An earlier trial of simvastatin resulted in severerhabdomyolysis with CPK in the 900-1000 IU/L range. Off statins,baseline LDL=212 with the atherogenic type B pattern on Vertical AutoProfile (VAP) (Atherotec Diagnostic Labs). A trial of Zetia® 10 mg daily+low dose Crestor® 5 mg daily was initiated but CPK rapidly climbedto >800 IU/L. This was accompanied by recurrence of severe statinmyalgia involving both thighs and calves. Due to significantrhabdomyolysis, Crestor® was promptly discontinued. While off statinsfor several months, CPK remained elevated with slight improvement (downto 705 IU/L) but myalgia had completely receded off Crestor®. Thepatient exhibited asymptomatic post-statin myositis (CPK 1-10×ULN) atthat time. Patient re-evaluated approx. four months later, at whichpoint LDL had returned to baseline (>200 mg %) off low-dose Crestor®. Atthat time, combination therapy with relatively high dose Crestor®, 20 mgdaily+Zetia® 10 mg daily +calcium HMB monohydrate, 2 g BID wasinitiated. Patient again re-evaluated 37 days later with repeat labs.Myalgia, previously continuous, had resolved except for very milddiscomfort climbing stairs. She resumed her regular routine walking witha friend 1-2 miles without stopping for rest and experienced no legdiscomfort with this activity. LDL had dropped to target at 49 and CPKhad fallen to 277 IU/L (26-192) on the new regimen.

Five months later, some residual but mild leg discomfort persisted witha rise in CPK to 378 IU/L. At the time, patient D-4's diabetes, managedby an endocrinologist, was uncontrolled (fasting glucose >200 mg %).Because of data suggesting that the area under blood level curve for HMBis reduced when ingested with glucose, HMB free acid was substituted forcalcium HMB monohydrate to improve absorption. The patient wasre-evaluated ten days later, at which point D-4 stated that she “feltbetter” on the free acid form (2 gelcaps TID, total dose 3 g daily),with a drop in CPK to 257 IU/L after ten days. Of note, her fastingblood glucose dropped to 100 mg % during the same time interval with noalteration of diet or diabetes medication.

Patient E-5

Male, 69 years old, underwent coronary bypass surgery ten years prior,with a history of mixed type hyperlipidemia, type 2 diabetes,hypertension and prior inferior myocardial infarction. Patient had ahistory of statin intolerance and stopped statin therapy due to statinmyalgia. He was otherwise compliant with all other medications.

Lipid panel obtained 9 months prior to enrollment revealed triglyceridelevels exceeding 500 mg %, thereby obscuring LDL measurements. At thattime, he was placed on fenofibrate to lower triglycerides and a repeatlipid profile 7 months later showed triglycerides reduced to 374, and anLDL=134. Unfortunately, he was fenofibrate intolerant and thismedication was stopped. Statin therapy with pravastatin 20 mg daily wasinitiated thereafter with the objective of using a very hydrophilic/lesslipophilic statin hoping that this would be less likely to cause statinmyopathy. The patient promptly developed statin myalgia and stoppedpravastatin.

When enrolled, the patient was no longer taking a statin and hadpersistent post-statin myalgia of the calves, despite statin withdrawal.He was given calcium HMB monohydrate, 2 g BID and instructed to resumepravastatin 1 week later. CPK after HMB treatment=110 IU/L (39-308). Thebilateral calf myalgia resolved rapidly and completely on HMB.

Patient F-6

Male, 66 years old, with a history of percutaneous coronaryintervention, right coronary artery, ten years prior. Medical problemsinclude type 2a hypercholesterolemia, type 2 diabetes, and hypertension.The patient had history of paroxysmal supraventricular tachycardia(PSVT) (arrhythmia) for which he underwent successful radiofrequencyablation. Hyperlipidemia was treated with atorvastatin, 40 mg daily andZetia®, 10 mg daily. At the time of enrollment, he complained of theonset of myalgia and short term memory loss after switching frompravastatin to atorvastatin to achieve target LDL. The myalgia involvedthe left shoulder, extending into the cervical region and occipitalmuscles of the skull. In addition to short term memory loss, the patienthad difficulty writing script but no focal motor deficit. All symptomswere present 6 months dating from the time conversion to atorvastatin.Upon enrollment, the patient was placed on a regimen of atorvastatin, 40mg daily, Zetia®, 10 mg daily, and calcium HMB monohydrate, 2 g BID. At2-month follow-up, all myalgia had completely resolved. His wife alsostated his short term memory loss had improved. Repeat LDL was 43 (threeyears prior, LDL had been 72 while taking Vytorin®, 10/40).

Patient G-7

Female, 70 years old, with type 2a hyperlipidemia, long-standing statinintolerance on multiple attempts, paroxysmal atrial fibrillation, PVC'swith normal stress test and benign hypertension. One month prior toenrollment: cholesterol (total) 254, LDL=169, HDL=56 and TG's=147. Atthat time, the patient underwent coronary angiography for what appearedto be ischemic chest pain but no obstructive coronary artery disease(CAD) was found. The patient, after this episode, was concerned abouther elevated LDL with the potential for future events and requestedenrollment into the SIM pilot study. SIM in her case was present in theform of disabling myopathy with profound global weakness. Uponenrollment, G-7 resumed statin therapy after an interval of greater thanfour years. In addition, she began calcium HMB monohydrate, 2 g BID.Approximately four weeks later, the patient remained free of allsymptoms of myalgia and muscle weakness. Repeat LDL=108, reduced from169. CPK=39 IU/L (29-168).

Patient H-8

Female, age 76, with a primary diagnosis of atrial fibrillation,controlled on anti-arrhythmic medication. She carried a secondarydiagnosis of type 2a hyperlipidemia, previously treated withsimvastatin. This medication was stopped due to bilateral leg myalgia,fully resolving post-statin calcium HMB monohydrate, 2 g BID. Onfollow-up encounter one month later, the patient remained completelyasymptomatic on this combination.

Patient J-10

Female, age 71, with mild-to-moderate non-obstructive coronary arterydisease with type 2a hyperlipidemia, hypertension and hypothyroidism.All conditions were under control with medical therapy. Eight monthsprior to enrollment, the patient was placed on Lipitor®, 10 mg daily.Since initiating statin therapy, she experienced bilateral thighachiness walking (especially through the mall) and climbing stairs. Sheconsulted an orthopedic surgeon but the symptoms became progressivelyworse. Upon enrollment, she was placed on calcium HMB monohydrate, 2 gBID and instructed to continue Lipitor®, 10 mg daily. At follow-up onemonth later, she stated there was complete resolution of bilateral thighpain.

Patient K-11

64-year-old female with severe familial hyperlipidemia, originally withLDL levels >300 mg % and B pattern (VAP) with a prior history ofstatin-induced rhabdomyolysis. Upon enrollment, patient had an LDL=282,and coincidentally, CPK=282 IU/L (29-168) on a regimen consisting ofCrestor0, 10, mg daily, Zetia®, 10 mg daily and Lovaza® 4 capsulesdaily. Although she was a medication failure at that dose, increasingthe dose of Crestor® would only result in worsening rhabdomyolysis. Shewas placed on calcium HMB monohydrate, 2 g BID and Crestor® wasincreased to 20 mg daily. At follow-up 47 days later: LDL=139 (50%reduction) and CPK=191 IU/L (32% reduction). The patient remainspain-free and exercises (weights and cardio) on a near-daily basis.

Patient L-12

Female, age 82, with coronary disease and prior coronary angioplasty(PCI 1st diagonal, bare metal stent, five years prior to enrollment).She had a history of statin intolerance with very rapid onset withvarious statins. As an alternative, she was managed with Zetia®, 10 mgdaily as monotherapy. This strategy effectively eliminated her statinmyalgia, specifically severe myalgia of the calves. Upon enrollment,LDL=122, HDL=37 and triglycerides=261 on Zetia®+diet, still not attarget. At that time, patient was placed on Crestor®, 5 mg daily+calciumHMB monohydrate, 2 g BID. Two months later, the patient was pain-freeand remains asymptomatic to date. Follow-up labs at two months: LDL=100,triglycerides=193 and CPK=87 IU/L (29-168).

Patient M-13

54-year-old male who underwent a 2-vessel PCl/stent procedure approx.1.5 years prior to enrollment (left anterior descending and rightcoronary arteries). He also had a history of peripheral vascular diseaseand underwent left superficial femoral artery angioplasty eight monthsprior to enrollment. Getting to target LDL was critical in this patientbut was impeded by biomarker(+) statin intolerance. Seven months priorto enrollment, patient was on Zetia® monotherapy but off statins due toSIM, LDL=244. Once again he was placed on a statin (Crestor®) but legmyalgia returned and, upon enrollment, CPK had risen to 320 IU/L (39-308). Crestor® was continued, and calcium HMB monohydrate, 2 g BID wasadded. On this combination, repeat lab was obtained four months later:LDL=114 (53% reduction), CPK=210 IU/L (39-308, 34% reduction). Allmyalgia had resolved at the time of a follow-up five months afterenrollment and patient remained asymptomatic/myalgia-free at least eightmonths after enrollment.

Patient N-14

Male, age 48, with historical hypercholesterolemia complicated by statinmyopathy in the form of muscle weakness involving extremities ratherthan myalgia. Medical problems included dysmetabolic syndrome and benignhypertension. About three years prior to enrollment, a Vertical AutoProfile (VAP) panel (Atherotech) revealed an LDL=109, type B pattern(small, dense, more atherogenic particles). At that time, treatmentconsisted of Zetia®, 10 mg daily and Welchol®, 625 mg daily. Repeat LDLa year prior to enrollment was 107. Because of co-morbidity placingpatient at higher risk for coronary artery disease (CAD), a statin agent(Livalo®, 1 mg daily) was added 8 months prior to enrollment. SIM withmuscle weakness eventually developed. Two months prior to enrollment,Livalo® was reduced to 0.5 mg daily but without improvement. Thepatient, in his own words, had “trouble picking things up.”

Upon enrollment, LDL=107, CPK=200 IU/L (30-200). Calcium HMBmonohydrate, 2 g BID was added at that time and statin therapy wascontinued. 13 days later, symptoms of muscle weakness had resolved andpatient was able to return to normal physical activity.

Patient 0-15

Male, age 70, with severe multivessel coronary disease, having undergonemultiple stent percutaneous coronary interventions (PCIS). Medicalhistory includes hyperlipidemia type 2a, adult onset diabetes mellitustype 2, hypertension and statin intolerance in the form of bilateralquadriceps myalgia. The patient's statin intolerance was mildly butpersistently biomarker positive. Because of his CAD history withmultiple PCI's, the patient remained on statin therapy despite daily legdiscomfort in return for optimal LDL control without further adversecardiac events. Lab upon enrollment: CPK=274 IU/L (30-200), LDL=30,TG's=324, HDL=29. Concurrent meds: Zetia®, 10 mg daily, Crestor®, 5 mgon alternate days and Lovaza® 4 g daily. After four weeks on combinedstatin therapy and calcium HMB monohydrate, 2 g BID, there was completeresolution of all quadriceps/thigh pain. Lab 2 months post-enrollment:LDL=53 (at target), CPK=310 IU/L. Discussing elevated CPK with patient,it was learned that he was now engaged in a 5 days/week weight program(6 machines, 50 reps to failure). This program is likely to cause CPKspill secondary to muscle micro-trauma (similar to patient A-1). Patientadvised to adhere to a weight program combined with more cardio withrest periods to allow recovery. He was also converted to HMB free acid,1 g TID for the purpose of evaluating its tolerance and reportedlysuperior absorption. Three months post-enrollment, he remainedcompletely symptom-free of statin myalgia/myopathy.

Patient P-16

63-year-old male with a history of severe multi-vessel coronary diseasepresenting as unstable angina who underwent 4-vessel coronary bypasssurgery with left internal mammary artery approx. 3 years prior toenrollment. Medical history included hyperlipidemia 2a and paroxysmalatrial fibrillation. Lipid management post-coronary bypass includedatorvastatin. About a year prior to enrollment, initial symptoms ofstatin myopathy appeared: bilateral thigh and hip adductor paincontinuous at rest and with activity. Patient was converted tosimvastatin without relief in symptoms.

Upon enrollment, patient was prescribed simvastatin +calcium HMBmonohydrate, 2 g BID. Lab at that time: LDL=79, CPK=225 IU/L (35-245).Sixteen days after enrollment, patient no longer had any thigh pain butthere was a persistent groin “stiffness” that disappeared after acardio/treadmill workout. These residual symptoms are not truly typicalof statin myalgia.

Example 3 In-Patient treatment of Acute Rhabdomyolysis

HMB administration is used to treat acute rhabdomyolysis in anin-patient setting.

Acute rhabdomyolysis is a rare but extreme and potentiallylife-threatening disorder that can occur in all groups in a setting ofdehydration, trauma, and in younger age groups, intense exercise. Statinagents have also been shown to cause acute massive rhabomyolysissyndrome (a form of statin myopathy) resulting in acute kidney failureand hemodialysis. At this time there is no known method of reversingrhabomyolysis apart from bed rest and hydration.

Protocol: measure patient's CPK; if value exceeds 10 times the upperlimit of normal (200 IU/L, depending on laboratory-specific establishednormal range), initiate the following:

-   -   1. Admit to ICU;    -   2. Initiate IV 0.9% saline at 165 ml/hour;    -   3. Initiate HMB free acid (gel form), dose 6 g twice daily for 3        days;    -   4. Lab: CPK, BUN, creatinine, glucose and electrolytes every 12        hours for 3 days.

Outcome: Patients' CPK is reduced below 200 IU/L within 3 days.

Example 4 Treatment of Statin-Induced Short-Term Memory Loss with HMB

HMB administration is used to treat short-term memory loss, an unusualside effect resulting from statin administration. Patient F-6, describedin the pilot study of Example 2, exhibited this side effect. In F-6'scase, symptoms began shortly after starting atorvastatin and mostlyresolved with the administration of HMB. Here, HMB is used to resolvesimilar short-term memory loss exhibited by patients taking statins.

Protocol: Patient describes short term memory loss after startingstatin. Initiate the following steps:

-   -   1. Assess memory loss with standardized neuro-psychometric        testing as baseline status;    -   2. Initiate calcium HMB monohydrate, 2 g twice daily; or calcium        free acid gel, 1 g three times daily;    -   3. Continue statin therapy with no dose change;    -   4. Obtain baseline lab (lipid panel, CPK, liver        function/metabolic profile) and repeat in 12 weeks;    -   5. Reassess memory status in 12 weeks repeating psycho-metric        testing and comparing to baseline study.

Outcome: Patients exhibit reversal of some or all short-term memory lossby HMB treatment within two months. Comparison of pre- and post-therapyneuropsychometric testing will be statistically analyzed (chi-squared,p-value).

Example 5 Treatment of Statin-Induced Abnormal Liver Function Using HMB

Elevated liver function tests (LFTs) are common in statin users. Thepresence of elevated transaminases, commonly the transaminases alaninetransaminase (ALT or SGPT) and aspartate transaminase (AST or SGOT), areindicators of liver damage. Terms for this condition includetransaminasemia and transaminitis, Normal ranges for both ALT and ASTare 8-40 U/L with mild transaminesemia noted to the upward numericallimit of 250 U/L. Here, HMB is administered to normalize abnormal liverfunction tests and reverse transaminitis.

Protocol: Protocol: Patient must exhibit ALT and AST levels in excess oftwice the upper limit of normal to enrol. Once enrolled, initiate thefollowing steps:

-   -   1. Initiate calcium HMB monohydrate, 2 g twice daily or HMB free        acid (gel form), 1 g three times daily;    -   2. Continue statin agent with no dose change;    -   3. Repeat liver panel in 3 months and compare to baseline.

Outcome: LFTs return to normal (ALT/SGPT less than 40 U/L, AST/SGOT lessthan 40 U/L) within 3 months of beginning HMB treatment.

Example 6 Treatment of Statin-Induced Glucose Intolerance Using HMB

Glucose intolerance with hyperglycemia/increased risk for diabetes,probably related to insulin resistance, has been reported in statinusers, especially lipophilic statins such as rosuvastatin, less so inhydrophilic statins such as pravastatin. Here, HMB administration isused to treat statin-related glucose intolerance.

Protocol: type 1, 1.5, and 2 diabetics with hemoglobin A1C at orexceeding 6.5% are eligible; also eligible are hyperglycemic/increasedrisk for diabetes patients not on diabetic treatment but with ahemoglobin A1C at or exceeding 5.7%; patients with critical valuefasting blood glucose and hemoglobin A1C levels are excluded. Onceenrolled, the following steps are initiated:

-   -   1. Continue statin and diabetic medications with dosages        unchanged;    -   2. Initiate calcium HMB monohydrate, 2 g twice daily, or HMB        free acid (gel form), 1 g three times daily;    -   3. Repeat fasting blood glucose and hemoglobin A1C in 3 weeks        and 6 weeks;

Outcome: Patients exhibit reduction of hemoglobin A1C to levels below6.5% in diabetics and 5.7% in hyperglycemics on dietary management(i.e., with increased risk for diabetes) within 6 weeks of beginning HMBtreatment, along with fasting blood glucose less than 100 mg % forhyperglycemic/non-diabetic management patients and less than 130 mg %for diabetic patients.

Example 7 Treatment of Statin-Related Cumulative Trauma Disorder UsingHMB

Cumulative trauma disorder, also known as chronic overuse syndrome, ischaracterized by muscle damage due to performing repetitive activitiesover time. Statin users are particularly vulnerable to cumulative traumadisorder due to impaired ability to heal chronically micro-traumatizedmuscle. Here, HMB is used to treat cumulative trauma disorder.

Protocol: Patients are enrolled if they qualify with symptoms thatinclude chronic muscle weakness and pain complemented by an occupationor lifestyle lending itself to chronic overuse syndrome (e.g.,construction workers, etc.). All patients are currently on statins.Initial documentation of strength levels and pain severity are required.Pain is evaluated using the Verbal Numerical Rating Scale (VNRS).Strength is measured using the Manual Muscle Testing/5-point scale.Additionally, grip strength is measured using a dynamometer. Onceenrolled, the following steps are initiated:

-   -   1. Obtain baseline lab including lipid panel and CPK-MM levels;    -   2. Continue statin with dose unchanged;    -   3. Continue repetitive activity in question at the same level of        intensity;    -   4. Initiate calcium HMB monohydrate, 2 g twice daily, or HMB        free acid (gel form, 1 g three times daily;    -   5. Re-evaluate pain severity and strength levels of patient        three weeks and six weeks after enrollment, statistically        comparing pain severity and strength levels against baseline        (p-value, Chi-squared);    -   6. Repeat baseline lab six weeks after enrollment.

Outcome: Patients exhibit reduced pain severity and increased strengthlevels within 6 weeks of beginning HMB treatment.

Having described the invention in detail and by reference to specificembodiments thereof, it will be apparent that modifications andvariations are possible without departing from the scope of theinvention defined in the appended claims. More specifically, althoughsome aspects of the present invention are identified herein asparticularly advantageous, it is contemplated that the present inventionis not necessarily limited to these particular aspects of the invention.

1.-32. (canceled)
 33. A pharmaceutical formulation comprising a statinside effect-alleviating amount of β-hydroxy β-methylbutyrate (HMB), or apharmaceutically acceptable salt thereof, in combination with: (a) 10 to80 mg atorvastatin; (b) 5 to 40 mg rosuvastatin; (c) 10 to 80 mgpravastatin; (d) 5 to 80 mg simvastatin; (e) 10 to 80 mg lovastatin; 1to 4 mg pitavastatin; or (g) 20 to 80 mg fluvastatin; or apharmaceutically acceptable salt thereof.
 34. The pharmaceuticalformulation of claim 33, which comprises 10 mg, 20 mg, 40 mg, or 80 mgatorvastatin or a pharmaceutically acceptable salt thereof.
 35. Thepharmaceutical formulation of claim 33, which comprises 5 mg, 10 mg, 20mg, or 40 mg rosuvastatin or a pharmaceutically acceptable salt thereof.36. The pharmaceutical formulation of claim 33, which comprises 10 mg,20 mg, 40 mg, or 80 mg pravastatin or a pharmaceutically acceptable saltthereof.
 37. The pharmaceutical formulation of claim 33, which comprises10 mg, 20 mg, 40 mg, or 80 mg simvastatin or a pharmaceuticallyacceptable salt thereof.
 38. The pharmaceutical formulation of claim 33,which comprises 10 mg, 20 mg, 40 mg, or 80 mg lovastatin or apharmaceutically acceptable salt thereof.
 39. The pharmaceuticalformulation of claim 33, which comprises 1 mg, 2 mg, or 4 mgpitavastatin or a pharmaceutically acceptable salt thereof.
 40. Thepharmaceutical formulation of claim 33, which comprises 20 mg, 40 mg, or80 mg fluvastatin or a pharmaceutically acceptable salt thereof.
 41. Thepharmaceutical formulation of any one of claims 33-40, wherein thestatin-side effect-alleviating amount of HMB or a pharmaceuticallyacceptable salt thereof is 4 to 6 grams.
 42. The pharmaceuticalformulation of claim 41, wherein the statin-side effect-alleviatingamount of HMB or a pharmaceutically acceptable salt thereof is 4 grams.43. The pharmaceutical formulation of claim 41, wherein the statin-sideeffect-alleviating amount of HMB or a pharmaceutically acceptable saltthereof is 6 grams.
 44. The pharmaceutical formulation of claim 33,wherein HMB is calcium HMB monohydrate.
 45. The pharmaceuticalformulation of claim 33, wherein HMB is HMB free acid.
 46. A method fortreating cumulative trauma disorder with myalgia/myositis, repetitiveuse disorder with micro-traumatic myalgia/myositis, acute or chronicrhabdomyolysis, statin-induced glucose intolerance, or statin-inducedshort-term memory loss, the method comprising administering to asubject: (a) a statin side effect-alleviating amount of β-hydroxyβ-methylbutyrate (HMB), or a pharmaceutically acceptable salt thereof;and (b) at least one of: (i) 10 to 80 mg atorvastatin; (ii) 5 to 40 mgrosuvastatin; (iii) 10 to 80 mg pravastatin; (iv) 5 to 80 mgsimvastatin; (v) 10 to 80 mg lovastatin; (vi) 1 to 4 mg pitavastatin; or(vii) 20 to 80 mg fluvastatin; or a pharmaceutically acceptable saltthereof.
 47. The method of claim 46, comprising administering to asubject 10 mg, 20 mg, 40 mg, or 80 mg atorvastatin or a pharmaceuticallyacceptable salt thereof.
 48. The method of claim 46, comprisingadministering to a subject 5 mg, 10 mg, 20 mg, or 40 mg rosuvastatin ora pharmaceutically acceptable salt thereof.
 49. The method of claim 46,comprising administering to a subject 10 mg, 20 mg, 40 mg, or 80 mgpravastatin or a pharmaceutically acceptable salt thereof.
 50. Themethod of claim 46, comprising administering to a subject 10 mg, 20 mg,40 mg, or 80 mg simvastatin or a pharmaceutically acceptable saltthereof.
 51. The method of claim 46, comprising administering to asubject 10 mg, 20 mg, 40 mg, or 80 mg lovastatin or a pharmaceuticallyacceptable salt thereof.
 52. The method of claim 46, comprisingadministering to a subject 1 mg, 2 mg, or 4 mg pitavastatin or apharmaceutically acceptable salt thereof.
 53. The method of claim 46,comprising administering to a subject 20 mg, 40 mg, or 80 mg fluvastatinor a pharmaceutically acceptable salt thereof.
 54. The method of claim46, comprising administering to a subject 4 to 6 grams HMB or apharmaceutically acceptable salt thereof.
 55. The method of claim 54,comprising administering to a subject 4 grams HMB or a pharmaceuticallyacceptable salt thereof.
 56. The method of claim 54, comprisingadministering to a subject 6 grams HMB or a pharmaceutically acceptablesalt thereof.
 57. The method of claim 46, wherein HMB is calcium HMBmonohydrate.
 58. The method of claim 46, wherein HMB is HMB free acid.